Pharmaceutical composition and use

ABSTRACT

A biologically active preparation for human or veterinary use for the selective blockade of opioid binding sites of the brain responsible for respiratory depression containing in a biologically active quantity the codeinone derivative of general formula (I) or its salt 
     R 1  means amino--, hydroxyl--, --NH--phenyl or --NH--CO--NH 2  groups, 
     R 2  means a hydrogen atom or a hydroxyl group. 
     The invention also covers a process for selective blocking the opioid binding sites of the brain responsible for respiratory depression by administering to a patient in need of an analgetic a preparation containing a codeinone derivative of general formula (I) or its salt preferably three times per day in doses of 2,5-5 mg. 
     A preferred feature of the inventions is an analgetic composition containing a codeinone derivative of general formula (I) and in a mass ratio of 1 : 2-3 morphine of the formula (IV) or an other, biologically equipotent agonist type opiate or opioid compound and optionally inert, pharmaceutically acceptable accompanying materials.

The subject of the invention is a biologically active composition forselective blocking of the opiate binding sites of the bran which areresponsible for respiratory depression, which contains codeinonederivatives of the general formula (I) or its salts in a biologicallyactive quantity.

In this specification the substituents of changing signification arealways the following:

R¹ means amino , hydroxyl-, --NH-phenyl or --NH--CO NH₂ --groups,

R² means a hydrogen atom or a hydroxyl group,

R³ means amino-, hydroxyl-, --NH--phenyl- or --NHCONH₂ groups or suchwhich can be transformed into said groups.

It is known that the morphine-like analgetics (opiates) act asrespiratory-depressants. On the course of acute toxicity investigationslethality of such compounds is attributed to this activity [Prog.Neurobiol. 33(1984)1-16; 22(1984) 345].

Interpretation of relations between respiratory depressant activity andopiate receptors is rather difficult. According to the presentconceptions there are several receptors which might participate inmediating this effect. However the relative contribution of variousreceptor populations mediating this effect is not clear enough. Sinceevaluating the respiratory parameters is complicated, selectivity of themethods is questionable and because of the big differences amongst thespecies the difficulties are further increased. The difficulties andproblems inherent in these methods partially explain the difference inreceptor assignments in opioid induced respiratory depression which haveappeared in literature.

Several biochemical and pharmacological data prove the heterogeneity ofthe opioid receptors both in the neurological system and in theperiferies [Trends. Neuro. Sci. 7.(1984) 31; Pharmac. Rev. 39 197-249(1987).]

The main receptors--marked μ, δ, . and σ receptors--show differentdispersity in the different tissues, have different ligand specifitiesand mediate different physiological processes. In recent times it wasclarified also that these main receptor types can be divided intosub-types. From these in the case of the μ type receptor it is possibleto distinguish μ₁ and μ₂ sub types. It is suggested that the μ₁ receptormediates the analgesic effects of opiates while the μ₂ mediates opioidinduced respiratory depression.

Identification of these two sub types of opioid receptors may be broughtabout by way of their binding capacity to opioid receptors of so calledhigh and low affinity. Ligands for μ₁ receptors are bound to the highaffinity (³ H)naloxone binding sites. (Their affinity constants arebelow nanomole concentrations.) The μ₂ receptors (low affinity bindingsites) mediates among others, opioid induced respiratory depression.(Their affinity constants are in the range of nanomole concentration orabove.)

Ligands are known which are capable to inhibit selectively the μ₁receptors. E.g. naloxonazine, oximorphazone, several other C-6morphinane derivatives and interestingly also some peptides (thechloro-methyl ketones of encephalines) are of this group.

As far as we are aware no compounds capable to block the μ₂ receptorswere known hitherto. It is our observation that codeinone, oxycodone anddihydrocodeinone derivatives substituted in position C-6 are bound in apartially irreversible manner to μ₂ receptors.

It has to be mentioned however that the existence of μ₁ and μ₂ receptorshas not yet found general acceptance. There were several who could notrepeat the experiment which serves as main proof namely that therespiratory depression caused by morphine is not inhibited by theselective μ₁ antagonist naloxonazine.

A further difficulty may be caused also by analysis of the complexaction of opiates on respiration. There are opiates known which aredepressing (μ-agonists: morphine etc.), others which are stimulating(receptor agonists: cyclazocine) and others which have dualistic(deprimating and stimulating) effects (partial antagonists: nalorphine).

The significance of identification of the μ₂ receptor would be in theoryand in practice that knowing the same there would be a possibility tosynthesize such compounds which would not have respiratory depressingwhile having considerable analgesic properties.

It is also known that there are certain dihydro morphinone and dihydrocodeinone derivatives substituted in position with hydrazone-, phenylhydrazone, dinitro phenyl hydrazo ne, semicarbazone andthiosemicarbazone groups as well as their 14 OH derivatives possessincreased analgesic activity as compared with the analogues which are6-unsubstituted (Hungarian patent application No. 56 85 or patentspecification 199.901).

The C-6 carbonyl group of the morphinane ketones is easily substitutedand earlier publications suggest that changes of this type in general donot influence the opioide character of the ligand.

It has been stated when investigating 6-substituted hydrazonederivatives of 14-hydroxy dhydro-morphnone [J. Med. Chem. 23 (1980) 674677, Pharm. Res. 3 (1986) 56 60, Life Sci., 40(1987) 1579-1588] thatboth the μ and the δ high affinity binding sites are irreversiblyblocked by these derivatives [J. Pharm. Exp. Ther. (1980) 214 and455-462]. It has been shown by pharmacological tests that irreversibleblocking of this receptor is manifested in the case of agonists in along-lasting analgesic effect, while in the case of antagonists theanalgetic activity of morphine is blocked for a long period of timewhile however the protection against lethal respiratory depression doesnot take place. [Life Sci. 31 (1983) 1389-1392, Science 208 (1989)514-516]. It has thus been stated that the opiate analgesia is mediatedby the common receptor named μ₁. Thus it would be a most desirable taskfor pharmaceutical planning to separate the analgetic effect from otheropiate effects.

When starting work according to our invention we studied different C-6substituted (hydrazone , phenylhydrazone , dinitro-phenylhydrazone-,oxime-, semicarbazone-) derivatives of dihydro morphinone and dihydrocodeinone on brain membranes of rats. The C-6 substitution did notchange their affinities to (³ H)naloxone binding sites in the case ofsubstituents of small size, while the affinity decreased in case ofsubstituents having a greater volume.

We stated that all tested C-6 substituted derivatives of oxymorphone anddihydromorphinone are blocking irreversibly, in a dose-dependent mannerthe specific bondage of (³ H)naloxone at isotope concentrations of 1 nMand this concerns the μ₁ receptor.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 sets forth structural formulas (I) compounds of the presentinvention, (II) a reactant for producing the compounds of formula (I),(III) a reactant for producing the compounds of formula (I), and (IV)the structural formula of morphine;

FIG. 2 is a graphical representation of specific binding of remaining(3_(H))naloxone of various compounds to dihydromorphinone anddihydrocodeinone;

FIG. 3 is a graphic representation specific binding of remaining (3_(H))naloxone of various compounds to dihydromorphinone and dihydrocodeinone;

FIGS. 4, 5 and 6, are graphical representation showing the Scatchardtransformations of the saturation binding isotherms of (3_(H)) naloxonespecific binding after pretreatment with dihydrocodeinone derivatives.

We have found surprisingly that oxycodone and dihydrocodeinonederivatives of general formula (I) are irreversible inhibitors or adose-dependent manner of specific binding of (³ H)naloxone at isotopeconcentrations of 1 nM and they have a lower affinity to the (³H)naloxone binding sites as compared with the corresponding morphinederivatives.

We ascertained however that at isotope concentrations of 10 nMpreincubation with these dihydrocodeinone derivatives blocks thespecific binding of (³ H)naloxone irreversibly and completely, as wellseen from saturation isotherms of (³ H)naloxone (preincubation of themembranes with these dihydrocodeinone derivatives followed by washing).It is essential that this involves the binding site of low affinity (μ₂)which is responsible for respiratory depression.

In our pharmacological tests based on the above we searched the replywhether the derivatives of general formula (I) would be exempt fromrespiratory depression actions which are presumably mediated by the μ₂receptor. Starting from the fact that toxicity of morphine is attributedto respiratory paralysis, we conducted toxicity tests of the abovecompounds and morphine on rats to get indirect information on the natureof the respiratory depressant activity. From the classical opiatespectrum we investigated along with the analgetic effect the sedativeaction as well.

We verified that the codeinone derivatives of general formula (I)significantly inhibit the lethal respiratory depression caused bymorphine (e.g. on rats), when increasing the LD₅₀ value measured onmorphine controls in the average to its twofold.

On the basis of the tables shown in the experimental examples we alsocan state that a part of the compounds stimulated in small dose rangesthe frequency of respiration and some even the amplitude, administeredi.v. and s.c. For example the oxycodone-semicarbazone and -oxime whenused in small doses considerably increase the respiration number and insome tests they reduced the depressant effect of morphine. In allexperiments we reversed respiration with naloxone to prove that thedepression was mediated by an opiate receptor. When administeringtogether the morphine effect was slightly inhibited in a 100 μg/kg dose.Oxycodone hydrazone increases both the volume and the frequency ofrespiration in an 50 μg/kg dose. When administered after morphine apartial reversal takes place. While somewhat depressing respirationoxycodone phenyl-hydrazone partially antagonizes the effect of morphine.It has to be mentioned that amongst the referred "mother compounds"dihydrocodeinone and oxycodone cause respiratory depression in 50-2500μg/kg and 10-2500 μ/kg s.c. doses. Both compounds unambiguouslypotentiate the respiratory depression effect of morphine.

The above experiments suggest that the codeinone derivatives of generalformula (I) according to our invention block selectively the opioidbinding sites of the brain which are mediating respiratory depressionand thus they can be used both in human and in veterinary preparationsin all cases where such blocking is necessary.

Thus the codeinone derivatives of general formula (I) can be used asactive ingredients in analgetic preparations without the appearance oflethal respiratory depression after longer treatment or higher doses.

The derivatives of general formula (I) also can be used preferably incombinations according to our invention. Thus it is specificallyimportant to our view that when administered together with morphine therespiratory depression can be decreased and the lethal effect can beavoided. Thus it is possible to administer morphine in prolonged andhigher doses in cases where the patient needs it without the occurrenceof lethal respiratory paralysis.

In preparation where morphine and the codeinones of general formula (I)are applied together the mass proportion of morphine : codeinonederivative amounts to 1 : 2-3.

Instead of morphine biologically equipotent amounts of other opiates ofthe agonist type or opioid compounds can be used in these combinationpreparations. Such compounds are e.g. morphinanes, benzomorphanes,opioid peptides or other pentacyclic compounds with morphine activity.

In addition to the above active ingredients the compositions accordingto our invention contain inert, pharmaceutically acceptable additivecompounds.

A further subject of our invention consists in a method to selectivelyblock opioid binding sites of the brain which are responsible fordepression of respiration by way of ad ministering to the patient inneed of such treatment a composition containing a codeinone derivativeof general formula (I) or its salt preferably in a 3×2,5--5 mg dailydose.

It is preferable to use the product in the form of i.m., i.v., orepidural injections it is however possible to use other dosage forms aswell.

A further subject of our invention is a process for the preparation of abiologically active composition containing codeinone derivatives ofgeneral formula (I) by reacting a ketone of the general formula (II)with a hydrazine derivative of the formula (III) by admixing kodeinonederivatives of the general formula (I) [alone or applied together with 1: 2-3 mass ratio of morphine or some other opiate or opioid compound ofthe agonist type]- with additive or auxiliary compounds usually appliedin pharmaceutical production for human or veterinary purposes so as toformulate compositions capable to block the opioid binding sitesresponsible for respiratory depression, preferably analgesics.

According to our invention the codeinone derivative of general formula(I) can be present n the form of its salt formed with mineral or organicacids preferably phosphoric acid, hydrochloric acid.

According to our invention it is possible to use the compounds in theform of their cis and/or trans isomers.

We have thus stated--as compared with the molecules protected in ourHungarian Patent No. 199.901--that according to our invention it is onlypossible to use a distinct, limited part of the 6-substitutedderivatives protected there.

It is not possible to use the big group of morphinane derivatives. Thusthe selective binding exposed according to our invention represents aproperty, the recognition of which constitutes the essential basis ofour invention and on the basis of this new point of view the selectionof outstandingly useful compounds out of the bigger range of others.

According to our knowledge the oximes falling under general formula (I)have never been described as pharmaceuticals at all.

The details of our invention are illustrated in the Examples.

EXAMPLES OF COMPOSITIONS

Compositions containing the following active ingredients are preparedwith usual additive material and methods:

                  TABLE                                                           ______________________________________                                                            tablet or                                                                              im. or iv.  epidur.                                   Compound       capsule  sc. inj.                                                                             inj. inj.                                 ______________________________________                                        I.1. Oxycodone-oxide                                                                              5        2      1    0,5                                       phosphate                                                                I.2. Oxycodone-oxime.                                                                             2        0,5    0,1  0,1                                       HCl +          5,0      5,0    5,0  1,0                                       morphine.HCl                                                             I.3. Oxycodone-semi-                                                                              2,5      1      0,5  0,1                                       carbazone-bi-                                                                 tartarate                                                                I.4. Oxycodone-phenyl-                                                                            2,5      1      0,5  0,1                                       hydrazone.HCl                                                            I.5. Oxycodone-     2,5      1      0,5  0,1                                       hydrazone.HBr                                                            I.6. Oxycodone-semi-                                                                              2,5      1      0,5  0,1                                       carbazone.HCl +                                                                              5,0      5,0    5,0  1,0                                       morphine.HCl                                                             I.7. Oxycodone-phenyl                                                                             2,5      1      0,6  0,1                                       hydrazone.HCl +                                                                              5,0      5,0    5,0  1,0                                       morphine.HCl                                                             I.8. Oxycodone-     2,5      1      0,5  0,1                                       hydrazone.HCl +                                                                              5,0      5,0    5,0  1,0                                       morphine.HCl                                                             I.9. Dihydrocodeinone-                                                                            10,0     5,0    2,0  1,0                                       oxime phosphate                                                          I.10.                                                                              Dihydrocodeinone-                                                                            5        2,5    1    0,1                                       oxime.HCl +    5,0      5,0    5,0  1,0                                       morphine.HCl                                                             ______________________________________                                    

The dose of the active ingredient is given in relation to the base, thesize is mg/formulated unit (tablet, ampoule).

EXAMPLE I.11.

Tablets of the following composition are prepared with usual methods:

    ______________________________________                                        Salt of the active ingredient                                                                    5,0    mg                                                                            (calculated as base)                                Lactose            60.0   mg                                                  Starch             30.0   mg                                                  Magnesium stearate 1,0    mg                                                  Talc               3,0    mg                                                  ______________________________________                                    

II. Binding Tests

Methods:

Membrane preparation: A crude membrane fraction from rat brain (PVG/Cstrain) was prepared [Mol. Pharm.11 (1975) 340-351 and the proteincontent was defined [Anal. Biochem. 72(1976) 248-254).

Description of the binding essay:

The membrane suspension (200-400 μg protein) was incubated with thespecific radioligand for 1 hour on ice. Incubations were terminated byrapid filtration under vacuo followed by washing with ice cold tris HClbuffer (50 mM, pH 7,4). Radioactivity was measured in a toluene basedscintillation mixture on a LKB Minibeta Liquid ScintillationSpectrophotometer. Nonspecific binding was defined in the presence of 10μM unlabeled naloxone. All assays were performed in triplicate andrepeated several times. K_(i) values were determined from equilibriumexperiments and calculated with the Tshang-Prusov equation. The datawere evaluated using the Ligand program [Anal. Biol. Chem. 107 (1980)220-239](Data shown on Table III/1).

Determination of wash-resistant binding:

After preincubation a thorough washing was performed. [Life Sci. 32(1983) 2777-2784]. Control values are represented by the specificbinding of (3H)naloxone to membranes preincubated with a buffer andtreated in the same way. Heterologous displacement experiments were usedto evaluate the affinity of the investigated compounds for (³ H)naloxonebinding sites. Results are shown in Table II/2.

II.1. BINDING TEST

                  TABLE II/1                                                      ______________________________________                                        Affinity constants (K.sub.i nM) of different opioid ligands in                competition assays                                                                   hydra-                                                                              phenyl-   semi                                                          zone  hydrazone carbazone oxime salt                                   ______________________________________                                        oxymorphone                                                                            2       20        4        2    sulfate                              dihydro- 6        5        3        2    sulfate                              morphinone                                                                    oxycodone                                                                              800     1150      588     32    HCl                                  dihydro- --      323       --      52    HCl                                  codeinone                                                                     ______________________________________                                         membranes were incubated with (.sup.3 H)naloxone (1 nM) and with              increasing concentrations of the ligands.                                

Evaluation:

The oxime derivatives exhibit the highest affinity for (³ H)naloxonebinding sites. The codeinone and dihydrocodeinone derivatives havesubstantially higher K_(i) values.

II.2. ESSAY ON WASH-RESISTANT BINDING

                  TABLE II/2                                                      ______________________________________                                        Affinity constants of oxycodone and                                           dihydrocodeinone derivatives                                                  Example    Compound.HCl      K.sub.i (nM)                                     ______________________________________                                        IV.2.      Oxycodone         127                                              IV.3.      Oxycodone-oxime    32                                              IV.5.      Oxycodone-semicarbazone                                                                         588                                              IV.8.      Oxycodone-phenylhydrazone                                                                       1150                                                        Dihydrocodeinone  476                                              IV.1.      Dihydrocodeinone-oxime                                                                           53                                                         Dihydrocodeinone-phenyl-                                                                        323                                                         hydrazone                                                          ______________________________________                                         The membranes were preincubated with (.sup.3 H)naloxone (1 nM) and with       increasing concentrations of tested compounds and the specific binding of     the remaining (.sup.3 H)naloxone was measured after several washings. The     date given represent the average of 2-4 data observed.                   

The codeinone derivatives were measured in 10 μM preincubationconcentrations. Evaluation: Table V. shows that the compounds of generalformula (I) are week, irreversible inhibitors of specific binding of (³H)naloxone at 1 nM concentration, especially on high activity receptors.At higher concentrations the situation is reversed and they inhibitmainly the low affinity receptors.

As it is seen in FIG. VI. the remaining (3H)naloxone specific binding issignificantly decreased at 10 nM isotope concentration as a result ofpreincubation with dihydro codeinone derivatives, while this decrease israther small if preincubation takes place with dihydro morphinonederivatives.

It was already shown previously [Life Sci.40 (1980) 1579-1588, J. Pharm.Exp. Ther.214 (1980) 455-462] that preincubation with hydrazonederivatives of oxymorphone and naloxone irreversibly inhibits the highaffinity (³ H)naloxone component, whereby the low affinity componentremains unchanged. As seen on Table II/1., the oxycodone and dihydrooxycodone derivatives show a lower affinity to the (³ H)naloxone bindingsites as compared with the correspondent morphine derivatives, if theisotope concentration is low.

These ligands however strongly inhibit at higher (10 nM) concentrationsthe (³ H)naloxone specific binding. This is why we studied the effect ofpreincubation with these derivatives on saturation isotherms of (³H)naloxone.

FIG. VII. shows the Scatchard transformations of the saturation bindingisotherms of (³ H)naloxone specific binding after pretreatment withdihydrocodeinone derivatives and with buffer only as a control. From theScatchard analysis the result is clearly seen, that after preincubationand intensive washings the low affinity receptor effect almostcompletely disappears.

III. PHARMACOLOGICAL TESTS

It is characteristic for the compounds that their greater part shows asubstantial and some a light agonist (analgetic or sedative) effect(Tables No. 1,2,3).

III.1. ANALGETIC EFFECTS

Comparison on the basis of data obtained in 4 tests on rats and mice(ED₅₀ mg/kg):

                  TABLE III/1                                                     ______________________________________                                                             tail    writhing                                                                             algolyt.                                              hot plate                                                                              flick   test   test (rat)                                compound    (rat)    (rat)   (mice) 100% activity                             ______________________________________                                        Oxycodone-oxime.                                                                          1,8      1,0     0,11   10,0*                                     phosphate                                                                     Oxycodone-semi-                                                                           0,58     0,35    0,15   5,0*                                      carbazone.                                                                    bitartarate                                                                   Oxycodone-phenyl-                                                                         0,8      1,2     1,2    10,0*                                     hydrazone.HCl                                                                 Oxycodon-   0,46     0,65    0,35   10,0*                                     hydrazone.HBr                                                                 Oxycodone-thio-                                                                           8,5      4,5     --     100,0                                     semicarbazone.                                                                HCl                                                                           Dihydrocodeinone-                                                                         0,38     0,35    --     10,0*                                     semicarbazone.                                                                HCl                                                                           Dihydrocodeinone                                                                          2,4      2,3     --     10,1**                                    phenyl hydrazone.                                                             HCl                                                                           Dihydrocodeinone-                                                                         4,2      3,7     0,38   25,0*                                     oxime.phosphate                                                               Dihydrocodeinone                                                                          1,7      0,6     --     5,0                                       thio-semicar-                                                                 bazone.HCl                                                                    Morphine    3,6      1,8     0,45   15,0                                      Oxycodone   0.92     0,68    0,45   2,2                                       Dihydrocodeinone                                                                          2,2      0,98    0,9    4,9                                       ______________________________________                                         *catalepsy                                                                    **convulsion                                                             

Methods:

Eur. J. of Pharm. (1982) 239-241; Arzn. Forschung 38 (1938) 552. Thestrongest analgetic on the hot plate test is thedihydrocodeinone-semicarbazone (ED₅₀ :0,38 mg/kg hot plates, tailflick). On the algolytic test the oxycodone-oxime, -semicarbazone,-phenylhydrazone and -hydrazone are capable to total assuage of pain -though amidst the symptoms of the slight cathatony - practically in theorder of magnitude of morphine or the mother compounds (oxycodone,dihydrocodeinone).

III.2. TESTING ON SEDATIVE ACTIVITY

Inactine (35 mg/kg) was used as a base narcotic.

                  TABLE III/2                                                     ______________________________________                                        Sedative (narcosis potentiating effect                                        (ED.sub.500 % mg/kg) s.c. on rats                                             name                   ED.sub.500 % mg/kg*                                    ______________________________________                                        oxycodone-hydrazone.HBr                                                                              0,45                                                   oxycodone oxime.phosphate                                                                            0,5                                                    oxycodone-semicarbazone.HCl                                                                          1,5                                                    oxycodone-phenylhydrazone.HCl                                                                        1,5                                                    dihydrocodeinone-phenylhydrazone.HCl                                                                 3,5                                                    dihydrocodeinone-semicarbazone.                                                                      1,0                                                    bitartarate                                                                   morphine               1,75                                                   dihydrocodeinone       1,9                                                    oxycodone              1,2                                                    ______________________________________                                         *ED.sub.500 % = dose increasing narcosis to five times the control.      

The doses of the active ingredients are always given in relation to thebase.

Evaluation:

All investigation compounds potentiate the activity of Inactinestrongly. The duration of narcosis is most effectively prolongated byoxycodone-hydrazone and -oxime respectively.

III.3. INVESTIGATION OF PHYSICAL DEPENDENCY

                  TABLE III/3                                                     ______________________________________                                        "jumping test" on mice                                                                                       number % rela-                                            treatment naloxone  of jumps                                                                             tion of                                            7 × mg/kg                                                                         50 mg/kg  /mouse jumping                                 name       ip.       ip.       (average)                                                                            animals                                 ______________________________________                                        morphine   100       +         34,5   100                                     oxycodone-oxime.                                                                         2         +         2,7    70                                      phosphate                                                                                5         +         2,5    50                                      oxycodone- 1         +         1,5    50                                      hydrazone.HBr                                                                 ______________________________________                                    

The dose of the active ingredient is given related to the base.

Table III/3. shows the results of an informative physical dependencystudy on the jumping test on mice. The mice were treated for three dayswith a total of 7 times i.p. with a high dose of the compounds to betested and after the final injection the symptoms of withdrawal aregenerated by administration of a morphine antagonist, i.e. a constraintfor jumping is provoked. Morphine equivalent quantities were administered from the test compounds. In the case of morphine the dosewhich effects dependence with certainty amounts to 7×100 mg/kg. Withinthis group on administration of 50 mg/kg of naloxone the average jumpingrate amounted to 34,5 (total jumping number/jumping animals) and 100% ofthe investigated animals did jump. Oxycodone-semicarbazone-oxime andhydrazone respectively when administered in equi-analgetic doses did notresult but in a very low, almost negligible number of jumping reactionswhile 50 70% were participating. The capacity of dependence of thesecompounds is thus unusually low.

III.4. MORPHINE TOXICITY TESTS

Morphine and the test substances were administered together, s.c, torats. As seen from Table III/4. almost twice as much is needed frommorphine to develop the same mortality meaning that toxicity of morphineis decreased to almost its half as a result of the activity of effectivetest substances (oxycodone-oxime, - semicarbazone, -phenylhydra-zone,-hydrazone and dihydrocodeinone-oxime). Dihydrocodeinonesemicarbazoneand -phenyl-hydrazone are less active. Oxycodone and dihydrocodeinonepotentiate toxicity of morphine (!).

                  TABLE III/4                                                     ______________________________________                                        Change of morphine toxicity in the presence of                                test substances (on rats)                                                                                         Combi-                                                             Morphine   nation                                                    Dose     LD.sub.50 g                                                                              LD.sub.50 /                                               mg/kg    mg/kg      morphine                                  Name            s.c.     s.c.       LD.sub.50                                 ______________________________________                                        Oxycodone-oxime.phos-                                                                         15       620        2,2                                       phate                                                                         Oxycodone-semicarba-                                                                          50       580        2,0                                       zone.bitartarate                                                              Oxycodone hydrazone.HBr                                                                       10       650        2,3                                       Dihydrocodeinone-phenyl-                                                                      50       500        1,7                                       hydrazone.HCl                                                                 Dihydrocodeinone oxime.                                                                       25       750        2,6                                       phosphate                                                                     Oxycodone       10       160        0,57                                      Dihydrocodeinone                                                                              10       150        0,53                                      Morphine        --       280        1,0                                       ______________________________________                                         The doses of the active substances are given in relation to the base.    

III.5. EFFECTS ON RESPIRATION TEST ON RABBITS

Method:

Investigation was carried out on conscious rabbits of both sexes and of3-4 kg weight by way of a Marey-drum. Frequency and amplitude ofrespiration were quantitatively evaluated.

Morphine decreased both frequency and volume of respiration in 2,5-5mg/kg doses. Some results are shown in Table III/5.

                                      TABLE III/5                                 __________________________________________________________________________    Effects on respiration on conscious rabbits                                                        respiration                                                                            respira-                                                   dose μg/kg                                                                           volume   tion                                            Compound   s.c.      frequency/min.                                                                         effect                                          __________________________________________________________________________    Morphine.HCl                                                                             2500-5000 ↓↓                                                                   ↓↓                                                                  depression                                                 i.v., s.c.                                                         Dihydrocodeinone.                                                                         10-5500  ↓                                                                           ↓                                                                          depression                                      HCl        i.v., s.c.                                                         Oxycodone.HCl                                                                             10-2500  ↓                                                                           ↓                                                                          depression                                                 i.v., s.c.                                                         Oxycodone-semicarba-                                                                     100-500+  ↑↓                                                                    ↑                                                                           morphine-                                       zone.HCl   morphine*          inhibition                                      Oxycodone-hydra-                                                                         50                                                                 zone.HCl   50        ↑                                                                            ↑                                                                           slight                                                     (administered      reversion                                                  after morphine*)                                                   Oxycodone- 100-500   0    0   no change                                       phenylhydra-                                                                             1000      ↑                                                                            ↑                                                                           slight stym.                                    zone.HCl                                                                      __________________________________________________________________________     *Morphine dose in combinations amounts to 5 mg/kg.                       

III.6. EFFECT ON RESPIRATION TEST ON CONSCIOUS RABBITS

Method:

The method as described above in Example III.5 was used on consciousrabbits of 2,5-3 kg weight. Registration was continued for 3-4 hours.The samples were injected under the skin of the neck and the respirationparameters were registered at intervals of 10 minutes.

Type A test: Determination of the dose-effect diagram of the substances("low dose region" and "high dose region") between 0.01 to 2.5 mg/kgalone and after selection of particular dose values investigation ofmorphine prevention.

Type B test: Sequence of application was the following: 5 mg/kg morphinewere administered (causing with certainty respiratory depression) andafter 10-20 minutes it was investigated whether the depression could bereversed.

Type C test: Administration of 5 mg/kg of morphine and the investigatedsubstance together to clarify whether the substance is capable to reducethe effect of morphine.

Some of the results are shown in the following tables.

                  TABLE III/6                                                     ______________________________________                                        Oxycodone oxime (OX)                                                          OX dose                                                                              pretr.   morphine  pretr.                                              mg/kg  period   mg/kg     period resp. change                                 s.c.   min.     s.c.      min.   fr/min ampl.                                 ______________________________________                                        0.005  30       --        --     +30    +30                                   0.1    30       --        --     +47    +40                                   0.025  30       --        --     +28      0                                   0.5 +  10       --        --     -50    -50                                   naloxone                                                                      0.25   10       --        --     +50    +50                                   --     --       0.5       30     -15      0                                   --     --       1.0       30     -20      0                                   --     --       2.5       30     -39    -20                                   --     --       5.0       30     -47    -80                                                             120    -66    -80                                   A.                                                                            0.1    10       --        --     +57    +20                                                   +5        30     +71      0                                                             40     -29    -40                                   ______________________________________                                         pret = duration of pretreatment                                          

                  TABLE III/7                                                     ______________________________________                                        Oxycodone semicarbazone (OS)                                                  OS dose                                                                              pretr.   morphine  pretr.                                              mg/kg  period   mg/kg     period resp. change                                 s.c.   min.     s.c.      min.   fr/min ampl.                                 ______________________________________                                        0.01   10       --        --     +48      0                                          30       --        --     +51    +20                                   0.025  30       --        --     +51    +20                                   0.05   10       --        --     +50    +75                                   0.025  10       --        --     +48    +20                                          20        5        20     +24    -16                                          30                 30     +13    -20                                   0.50   10       --        --     +36      0                                          30       20        20     +10      0                                   ______________________________________                                    

                  TABLE III/8                                                     ______________________________________                                        Oxycodone phenylhydrazone (OP)                                                OP dose                                                                              pretr.   morphine  pretr.                                              mg/kg  period   mg/kg     period resp. change                                 s.c.   min.     s.c.      min.   fr/min ampl.                                 ______________________________________                                        A.                                                                            0.1    10       --        --     +33    +20                                   0.5    10       --        --     +16      0                                                   5         10     -17    -20                                          60                          0      0                                   B.                                                                            --     --       5         10     -40    -40                                   1.0                       20     -16    +15                                                             30      -6    +20                                   C.                                                                            0.25            5         20     +44    +20                                                             30     +92    +30                                   0.25            10        10     +23    +20                                   0.25            20        30      -8      0                                   ______________________________________                                    

                  TABLE III/9                                                     ______________________________________                                        Oxycodone hydrazone (OH)                                                      OH dose                                                                              pretr.   morphine  pretr.                                              mg/kg  period   mg/kg     period resp. change                                 s.c.   min.     s.c.      min.   fr/min ampl.                                 ______________________________________                                        A.                                                                            0.25   20       --               +150   +20                                          30       --               +127   +20                                                   5         10     -36    -30                                   C.                                                                            0.25            5         20     +30    +10                                   ______________________________________                                    

                  TABLE III/10                                                    ______________________________________                                        Dihydrocodeinone-phenylhydrazone (DP)                                         DP dose  pretr.   morphine pretr.                                             mg/kg    period   mg/kg    period resp. change                                s.c.     min.     s.c.     min.   fr/min                                                                              ampl.                                 ______________________________________                                        A.                                                                            0.01     10'      --       --      +85  0                                              20'      --       --      +96  0                                     0.025    10'      --       --     +114  0                                              20'      --       --     +114  0                                     0.05     10'      --       --     +132  0                                     C.                                                                            0.25 together     5        10'     +39  0                                                                20'     +19  0                                                                30'     -3   0                                                                50'     -4   0                                     ______________________________________                                    

The Table shows, the doses of 0.01 to 0.05 mg/kg considerably increasethe frequency without influence on the amplitude of respiration. Dosesof 0.25 mg/kg when administered together with morphine retard depressionto some degree.

IV. CHEMICAL PROCESS EXAMPLES

(Method: Hungarian patent specification No. 199.901)

IV.1. DIHYDROCODEINON-OXIME

1,5 g of hydroxylamine-chlorohydrage are reacted in 70 ml of water with3,0 g of dihydrocodeinone base for 3 hours and then adjusted to pH=9-10.The oxime precipitates as crystals, which are filtered, washed withwater and crystallized from propanol. The product amounts to 2,5 g.M.p.:265-266° C.

IV.2. 14-HYDROXY-DIHYDROCODEINONE-OXIME

The product of Example IV.1. is crystallized from aqueous ethanol. M.p.:194° C.

IV.3. 14-OH-DIHYDROCODEINONE-HYDRAZONE (TRANS)

5 ml of 100% hydrazone hydrate are heated with 2,0 g of14-OH-dihydrocodeinone inn 10 ml of dimethyl-formamide for two hours andthen poured into water. The crystalline product which precipitates isisolated and chromathographized on silicagel (chloroform-methanol 9:1,v/v). The pure fractions obtained by TLC eluating with the eluentchloroform: methanol: cc. ammonium hydroxide mixture 90:10:5 arecrystallized from methanol. M.p.:192-194° C.

IV.4. 14-OH-CODEINONE-HYDRAZONE

Using the method of Example IV.3. 1,8 g 14-OH-codeinone-hydrazone areobtained from 2,0 g of 14-OH-codeinone. The crude product contains twocomponents as shown by TLC using the eluant chloroform: methanol:cc.ammonium hydroxide 90:10:5. The main component can be obtained inpure state by way of preparative thin-layer chromatography. Crystallizedfrom ethanol m.p.: 212-215° C.

IV.5. 14-OH-DIHYDROCODEINONE-SEMICARBAZONE (TRANS)

According to the method described in Example IV.4. 3,2 g of the crudeproduct are obtained from 3,0 g of 14-OH-dihydrocodeinone, which is themixture of syn and anti isomers (cis:trans=1:1). By way ofcrystallization (chloroform - ethanol) the pure trans semicarbazone isobtained. M.p.: 236-238° C.

IV.6. 14-OH-DIHYDROCODEINONE-PHENYLHYDRAZONE (CIS)

Starting from 1,55 g of 14-OH-dihydrocodeinone 1,7 g of14-OH-dihydrocodeinone-phenylhydrazone are obtained with the processgiven in Example IV.3. M.p. after recrystallization: 174-176° C. Purecis isomer.

I will:
 1. A composition for achieving an opioid analgesic effect whileinhibiting respiratory depression, said composition comprising ananalgesic effective amount of a compound of the formula I: ##STR1##wherein R¹ is -OH, and R² is H or OH, or a pharmaceutically acceptablesalt thereof.
 2. Composition according to claim 1, wherein said compoundis dihydrocodeinone oxime or a pharmaceutically acceptable salt thereof.3. Composition according to claim 1, wherein said compound is14-hydroxy-dihydrocodeinone oxime or a pharmaceutically acceptable saltthereof.
 4. Method of achieving opioid analgesia while inhibitingrespiratory depression, comprising administering to a patient requiringthe same an analgesic effective amount of a compound of the formula I:##STR2## wherein R₁ is --OH, and R₂ is H or OH, or a pharmaceuticallyacceptable salt thereof.
 5. Method according to claim 4, wherein saidcompound or salt is administered about 3 times a day in doses of about2.5-5 mg.
 6. Method according to claim 5, wherein said compound or saltis administered along with an additional opioid agonist, whichadditional opioid agonist causes respiratory depression and saidadditional opioid agonist is used together with said compound of formulaI or its salt in a molar ratio of about 1:2-3.